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Background: Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders affecting millions worldwide. Despite the widespread adoption of next‐generation sequencing (NGS) panels, there remains a critical gap in the genetically diverse and understudied African populations. Methods: One hundred and thirty‐five South African patients affected by various IRDs underwent NGS using a custom‐targeted panel sequencing over 100 known genes. The panel was supplemented by in silico screening for a MAK‐Alu insertion and screening of seven functionally established deep intronic variants. Results: Through our combined screening strategy, we obtained a probable genetic diagnosis for 56% of the cohort. We identified 83 unique variants in 29 IRD genes underlying the disease, including 16 putative novel variants. Molecular findings prompted recommendations for clinical re‐examination in ten patients. Resolution rates varied across clinical classifications and population groups. Conclusions: This study reports the first use of a targeted NGS panel for IRDs in southern Africa, demonstrating a cost‐effective, customisable approach that optimises both diagnostic yield and resource efficiency, making it a valuable tool for IRD molecular characterisation in resource‐limited settings. Augmenting the panel by screening for variants relevant to South African patients allowed us to achieve a resolution rate in line with international studies. Our study underscores the importance of investigating diverse populations to bridge disparities in genomic research and improve diagnostic outcomes for underrepresented population groups. [ABSTRACT FROM AUTHOR]

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable disorder characterized by progressive degeneration of right ventricular myocardium, arrhythmias and an increased risk of sudden death at a young age. By linkage analysis, ARVC type 6 was previously mapped to a 10.6 cM region on chromosome 10p12-p14 in a large North American kindred. To date, the genetic defect that causes ARVC6 has not been identified. Methods We identified a South African family of 13 members with ARVC segregating as an autosomal dominant disorder. The diagnosis of ARVC was based on international diagnostic criteria. All available family members were genotyped with microsatellite markers at six known ARVC loci, and positional candidate gene screening was performed. Results Genetic linkage and haplotype analysis provided lod scores that are highly suggestive of linkage to the ARVC6 locus on chromosome 10p12-p14, and the narrowing of the critical region to ~2.9 Mb. Two positional candidate genes (ITG8 and FRMD4A) were screened in which defects could possibly disrupt cell-cell adhesion. A non-positional candidate gene with apoptosis inducing properties, LAMR1P6 (laminin receptor 1 pseudogene 6) was also screened. Direct sequencing of DNA from affected individuals failed to detect disease-causing mutations in the exonic sequences of the three genes investigated. Conclusion The narrowing of the ARVC6 critical region may facilitate progress towards the identification of the gene that is involved in ARVC. Identification of the causative genes for ARVC will contribute to the understanding of the pathogenesis and management of this poorly understood condition.